title: Recurrent deletion of 3p13 targets multiple tumour suppressor genes and defines a distinct subgroup of aggressive ERG fusion-positive prostate cancers.
abstract: Deletion of 3p13 has been reported from about 20% of prostate cancers. The clinical significance of this alteration and the tumour suppressor gene(s) driving the deletion remain to be identified. We have mapped the 3p13 deletion locus using SNP array analysis and performed fluorescence in situ hybridization (FISH) analysis to search for associations between 3p13 deletion, prostate cancer phenotype and patient prognosis in a tissue microarray containing more than 3200 prostate cancers. SNP array analysis of 72 prostate cancers revealed a small deletion at 3p13 in 14 (19%) of the tumours, including the putative tumour suppressors FOXP1, RYBP and SHQ1. FISH analysis using FOXP1-specific probes revealed deletions in 16.5% and translocations in 1.2% of 1828 interpretable cancers. 3p13 deletions were linked to adverse features of prostate cancer, including advanced stage (p < 0.0001), high Gleason grade (p = 0.0125), and early PSA recurrence (p = 0.0015). In addition, 3p13 deletions were linked to ERG(+) cancers and to PTEN deletions (p < 0.0001 each). A subset analysis of ERG(+) tumours revealed that 3p13 deletions occurred independently from PTEN deletions (p = 0.3126), identifying tumours with 3p13 deletion as a distinct molecular subset of ERG(+) cancers. mRNA expression analysis confirmed that all 3p13 genes were down regulated by the deletion. Ectopic over-expression of FOXP1, RYBP and SHQ1 resulted in decreased colony-formation capabilities, corroborating a tumour suppressor function for all three genes. In summary, our data show that deletion of 3p13 defines a distinct and aggressive molecular subset of ERG(+) prostate cancers, which is possibly driven by inactivation of multiple tumour suppressors.
authors.affiliation: Institute of Pathology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Antje
authors.initials: A
authors.lastname: Krohn
authors.forename: Annemarie
authors.initials: A
authors.lastname: Seidel
authors.forename: Lia
authors.initials: L
authors.lastname: Burkhardt
authors.forename: Frederic
authors.initials: F
authors.lastname: Bachmann
authors.forename: Malte
authors.initials: M
authors.lastname: Mader
authors.forename: Katharina
authors.initials: K
authors.lastname: Grupp
authors.forename: Till
authors.initials: T
authors.lastname: Eichenauer
authors.forename: Andreas
authors.initials: A
authors.lastname: Becker
authors.forename: Meike
authors.initials: M
authors.lastname: Adam
authors.forename: Markus
authors.initials: M
authors.lastname: Graefen
authors.forename: Hartwig
authors.initials: H
authors.lastname: Huland
authors.forename: Stefan
authors.initials: S
authors.lastname: Kurtz
authors.forename: Stefan
authors.initials: S
authors.lastname: Steurer
authors.forename: Maria C
authors.initials: MC
authors.lastname: Tsourlakis
authors.forename: Sarah
authors.initials: S
authors.lastname: Minner
authors.forename: Uwe
authors.initials: U
authors.lastname: Michl
authors.forename: Thorsten
authors.initials: T
authors.lastname: Schlomm
authors.forename: Guido
authors.initials: G
authors.lastname: Sauter
authors.forename: Ronald
authors.initials: R
authors.lastname: Simon
authors.forename: Hüseyin
authors.initials: H
authors.lastname: Sirma
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D045744:Cell Line, Tumor; D002872:Chromosome Deletion; D002893:Chromosomes, Human, Pair 3 / Q000235:genetics*; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D055785:Gene Knockdown Techniques; D016147:Genes, Tumor Suppressor; D005858:Germany / Q000453:epidemiology; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D009364:Neoplasm Recurrence, Local; D020411:Oligonucleotide Array Sequence Analysis; D015514:Oncogene Proteins, Fusion / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D011467:Prostate / Q000378:metabolism / Q000473:pathology; D011468:Prostatectomy; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D046888:Tissue Array Analysis
chemical_list: C486626:FOXP1 protein, human; D051858:Forkhead Transcription Factors; D015514:Oncogene Proteins, Fusion; D012097:Repressor Proteins; C515553:TMPRSS2-ERG fusion protein, human
keywords: 3p13 deletion; ERG; FOXP1; PTEN; RYBP; SHQ1; prostate cancer